Process for the production of coumarin derivatives



United States Patent Ofice 3,538,098 Patented Nov. 3, 1970 Int. Cl. C07d51/70 US. Cl. 260-268 9 Claims ABSTRACT OF THE DISCLOSURE Thisdisclosure describes new and useful pharmaceutical products particularlyuseful as coronary dilators. They can be designated as coumarinderivatives having the formula the radicals in each instance having thefollowing signifiand X represents hydrogen or a hydroxy group.

The present invention relates to new, pharmacologically valuablecoumarin derivatives and processes for their manufacture.

These new coumarin derivatives have the general formula wherein R meanshydrogen, lower alkyl, or phenyl, R stands for 6,7- or 7,8-positionedalkoxy, R represents lower alkoxy having 14 carbon atoms, In is theinteger 1, 2 or 3, A is a straight or branched alkylene radical having2-3 carbon atoms, A is a straight or branched alkylene radical having2-4 carbon atoms and Y stands for hydrogen, a hydroxy group or for theresidue O-C O The new coumarin derivatives are obtained in the knownmethods:

(a) By acylating, possibly in the presence of an acidbinding agent,coumarin derivatives of the general formula l rN wherein X stands forhydrogen or a hydroxy group, with an alkoxy benzoic acid of the generalformula or with a functional derivative, or

(b) By condensing, possibly in the presence of an acid-binding agent,coumarin derivatives of the general formula with an alkoxy benzoic acidhaloalkyl ester of the general formula hal-A20 00G wherein hal standsfor a halogen atom.

As low molecular alkyl radicals R and alkoxy radicals R in 6,7- or7,8-position or R are used particularly those having 1-4 carbon atoms.

If starting products are used in which the bridge member A, does notcontain any hydroxy group, the claimed process yields the correspondingmonoesters and if a hydroxy group is present, it yields mono anddiesters. According to the present invention, monoesters are obtained ifcoumarin starting materials are acylated with 1 mol alkoxy benzoic acidor the functional derivative; the corresponding diesters are obtained if2 moles of the latter are used. If diesters are prepared, theesterification may also be done in two steps, whereby in either stepvarious alkoxy benzoic acids or their functional derivatives may be usedas acylating agents. This technique permits the preparation of mixeddiesters that contain two different acyl radicals. When operatingaccording to the condensation process (b) of the present invention, onlymonoesters are obtainable, which, however, may also be converted intodiesters according to the esterification process (a) by means of asecond mol of the acylating agent, provided the intermediate member Acontains a hydroxy group capable of acylation.

The coumarine derivatives obtainable under the present invention arevaluable pharmaceutics. In particular, they are excellent coronarydilators and, in this respect, superior to other known substances havingsuch properties. Their salts are colorless, crystalline substances thateasily dissolve in water.

With respect to the change in the oxygen tension in the coronary veinousblood, the phamacological investigation of the vasodilator action on thecoronary vessels Was carried out in dogs according to the methodsdescribed by W. K. A. Schaper and his coworkers (see W. K. A. Schaper,R. Xhonneux, and J. M. Bogaard, Uber die kontinuierliche Messung desSauerstoifdruckes im venosen Coronarblut, Naunyn-Schmiedebergs Arch.exp. Path. u. Pharmak. 245, 383389 (1963)). The test preparations wereapplied intravenously to the narcotized and spontaneously breathinganimals. On these test conditions the dilatation of the coronaryarteries caused by the test sub- 10 rate was continuously measured byelectronic methods from systolic peaks of the arterial blood pressure.

The arterial blood pressure was measured in the known manner in thefemoral artery with the aid of an electronianometer of theStratham-strain-gauge type.

15 The following table gives the results of the pharmacologicalinvestigations which were carried through. The preparations were testedin the form of their respective dihydrochlorides Maximal increase inoxygen LDao -l mouse Dosage,

tension in the coronary Maximal change in the Maximal change in theveinous blood heart rate blood pressure mg./ kg. Preparation 1.v. 1.v.

In percent In minutes In percent In minutes In percent In minutescoumarin 2.0

coumarin 2. 0

In the preparation of drages and tablets containing as essential activeingredient the coumarin derivatives of our invention these substancesmay be admixed with the conventional solid tabletting adjuvants, such asstarch, lactose, talc and the like. Any of the tabletting materials andcarriers customary in pharmaceutical practice may be employed.

For the preparation of the injection solutions the hydrochlorides of thecournarin derivatives are particularly suited since they have mostly agood water-solubility. Injection solutions of water-insoluble productsmay of course be prepared in the conventional manner by concurrentlyusing well-known suspending agents, emulsifiers and/ or solubilizers.

For a better understanding of the nature and the objects of thisinvention, reference should .be made to the accompanying examples whichare of an illustrative rather than a limiting nature. Unless otherwisestated, all temperatures given are in degrees centigrade.

EXAMPLE 1 CHz-CHz-N NCH2CHzO-CO HaCO- 0 37.6 g. (0.1 mol)3-[B-(4-(pi-hydroxyethyl)-piperazino- [1]) ethyl]4-methyl-7,8-dimethoxy-coumarin are suspended in 200 cc. anhydrousbenzene and 10.1 g. (0.1 mol) triethylamine are added. Within 30minutes, a solution of 23 g. (0.1 mol) 3,4,5-trimethoxybenzoyl chloridein 100 cc. anhydrous benzene is added dropwise with stirring at roomtemperature. The mixture is stirred for 4-5 hours at this temperature.Subsequently, it is stirred under reflux for 2 hours and, while hot,separated triethylamine hydrochloride is filtered off with suction. Thefiltrate is washed with water, a 5% aqueous sodium hydrogen carbonatesolution and again with water and dried over anhydrous sodium sulfate.The solvent is now distilled off at 50 in the water-jet vacuum and theresidue, a lightyellow, viscous oil, is dissolved in little anhydrousethyl acetate, then etheral hydrochloric acid is added until congo paperturns blue. Thus, the dihydrochloride of the 3 [B (4(ii-3",4",5"-trimethoxybenzoxyethyl)-piperazino[1']) ethyl]4-methyl-7,S-dimethoxy-coumarin is obtained in the form of colorlesscrystals decomposing at 239-240".

Yield: 53 g.=82% of the theoretical.

The 3-[/3-(4'-(B hydroxyethyl) -piperazino[1'] )-ethyl]4-methyl-7,8-dimethoxy-coumarin used as starting material can beprepared as follows:

(a) 13 g. (0.055 mol) 3-(fi-hydroxyethyD-4-methyl-7,8-dihydroxy-coumarin (prepared according to the method described inChem. Abstr. 54, 24690 g. (1960)), 40 cc. glacial acetic acid and 36 cc.48% hydrobrornic acid are stirred at 110-115 for 5 hours. After coolingdown, the reaction mixture is poured into the fivefold quantity of waterand the precipitate which has settled out is filtered off with suction.The reaction product being still wet can be recrystallized from glacialacetic acid. Thus, 14 g. (=85 of the theoretical) 3-(B-bromoethy1)-4-methyl-7,8-dihydroxy-coumarin are obtained having a melting point of190. Analogously, the following products were prepared:

3- (p-bromoethyl) -4-n-propyl-7,S-dihydroxy-coumarin.

Melting point: 175-177.

3- (,B-brornoethyl) -4-phenyl-7 ,S-dihydroxy-coumarin.

Melting point: 211-213".

(b) 15 g. (0.05 mol) 3-(B-bromoethyl)-4-methyl-7,8- dihydroxy-coumarinare dissolved in 100 cc. dioxan and admixed with g. dimethyl sulfate.When passing nitrogen thru this mixture, a solution of 7 g. sodiumhydroxide in 20 cc. Water is added dropwise with stirring, at 3540".Stirring of the reaction mixture is continued at -40 until it does notshow an alkaline reaction any longer. After a further addititon of 25 g.dimethyl sulfate, again a solution of 7 g. sodium hydroxide in 20 cc.water is added dropwise. After the reaction mixture is no longeralkaline it is evaporated to dryness in the water-jet vacuum and theresidue is diluted with water. The precipitated reaction product isdissolved in ethyl acetate and the ethyl acetate layer is washed withdiluted sodium hydroxide solution, then dried and evaporated to drynessunder reduced pressure. Thus,3-(B-brornoethyD-4-methyl-7,8-dimethoxy-coumarin is obtained in the formof colorless crystals melting at 147-149".

Yield: 13 g. =79.3% of the theoretical.

Analogously to the process as described above, the followingintermediates can be prepared:3-(B-boromethyl)-4-n-propyl-7,8-dimethoxy-coumarin.

Melting point: 8790.

O 3-(;3-brom0ethyl)-4-phenyl-7,8-dimethoxy-coumarin.

Melting point: 163-165".

OOH:

l O OH:

(c) 32.7 g. (0.1 mol) 3-(fi-bromoethyl)-4-methyl-7,8- dimethoxy-coumarinand 13 g. (0.1 mol) N-(B-hydroxyethy1)-piperazine are dissolved in cc.chloro benzene. After the addition of 10.6 g. (0.1 mol) anhydrous sodiumcarbonate, the solution is stirred for 12 hours with boiling underreflux. After cooling down, precipitated sodium bromide is filtered offwith suction and the filtrate is evaporated to dryness under reducedpressure. The remaining oily crude product is crystallized by stirringit with little ethyl acetate. The crystallized product is filtered offwith suction and, for further purification, recrystallized from ethylacetate. Thus, 3-[B-(4'-hydroxylethyl-piperaziuofi'])-ethyl] 4methyl-7,8-dimethoxycoumarin is obtained having a melting point of210-212".

Yield: 34 g.'=90% of the theoretical.

Analogously, the intermediates of the following general formula can besynthetized:

General formula:

Analogously to the description given in the present example, paragraph1, the following compounds can be 7 8 prepared under the presentinvention from the intermedi- 28.4 g. (0.1 mol) 3-['-chloro-fl-hydroxypropyl]-4-methylates given above:7,8-dihydroxy-coumarin (prepared by condensing a-acetyl- Generalformula: 'y-chloromethyl-butyrolactone with pyrogallol, according to themethod described in the British Pat. 1,044,608), are dissolved withheating in 200 cc. dioxan. After cooling down to about 40, 40 g.dimethyl sulfate are added. Then,

R1 00313 with stirring in a nitrogen atmosphere, a solution of 42 g.

I potassium carbonate dissolved in 80 cc. Water is added CH2OH2 N OCHadropwise. The reaction mixture is stirred at 40 until a sample does notshow any longer a yellow tinge when H3CO 0 00113 admixed with dilutedsodium hydroxide solution, which 0 is the case after roughly 23 hours.When the mixture is OOHa diluted with Water, the reaction productseparates in the form of colorless needles. For purification purposes,the

crude product filtered off with suction is dissolved in chlo- MeltingPoint or decomposition point roform, the solution is washed with dilutedsodium hy- R1 i il g' g droxide solution and dried. After havingevaporated the chloroform solution to dryness, the3-[y-chloro-B-hydroxy- 3 3 :8%:g% propyl]4-methyl-7,8-dimethoxy-coumarinis obtained in CH 'CH20H2CH2 236 the form of colorless needles havlng amelting polnt of assass 20311; -orrionionionw 224 Yield: 27 g.=86.5% ofthe theoretical. ggli: ::8%:I% E) Analogously there are obtained:

15 C l-I -oHg6H2c H2O i 2 226-220 3 ['y chloro 3 hydroxypropyl] 4 npropyl 7,8

dimethoxy-coumarin. Melting point: 136-137. 3 [7 chloro ,8hydroxypropyl] 4 phenyl 7,8

dimethoxy-coumarin. Melting point: 142. 3 [7 chloro p hydroxypropyl] 4methyl 7,8 EXAMPLE 2 diethoxy-coumarin. Melting point: 136-138.

CH3 OCH;

CHzOHOH-CH2N N-CH2CH2-OOO OCH3 I HaCO 0 O OCHa OCHa 40.6 g. (0.1 mol)3-['y-(4'(/3-hydroxyethy1)-piperazino 31.2 g. (0.1n1ol)3-('y-chloro-B-hydroxypropyl)-4-methyl- [1'] B hydroxypropyl] 4 methyl7,8 dimethoxy 7,8-dimethoxy-coumarin and 13 g. N-(fi-hydroxyethyD-picoumarin are dissolved in 350 cc. anhydrouschloroform perazine are dissolved in 150 cc. chloro benzene and, andadmixed with 10.1 g. (0.1 mol) triethylamine. Within after the additionof 11 g. anhydrous sodium carbonate, one hour, 23 g. (0.1 mol)3,4,5-trimethoxy-benzoyl chlostirred at 120 for 7 hours. After coolingdown, the mixride, dissolved in 100 cc. anhydrous chloroform, are addedture is filtered off with suction from the precipitated sodropwise withstirring. After the exothermic reaction has dium chloride and thefiltrate is evaporated to dryness decayed, the solution is stirred at40-50 for another 2 under reduced pressure. T e de Productcrystallilif'lg ho l d d d d i d ith t Th hl out is st1rred with 100 cc.ethyl acetate for further purlfif Phase is Separated and washed withwater, a 5% cation, filter ed off with suction, then vacuum-dried. Thus,sodium hydrogen carbonate solution and once again with 3 (4 (I8hydroxyethyl) Plperazmon water. The chloroform solution is dried overanhydrous flroxy j Propyll 4 methyl dlmethoxy; Coumarm sodium sulfateand the solvent is distilled off at 50 under b T havmg a melting pomt142445 reduced pressure. The residue is dissolved in dilute aquef 3 7 ofl f d l ous hydrochloride acid and the aqueous, hydrochloric 0 owmg merme 1a es can 6 prepare ana solution is extracted with ethyl acetatefor purification g i formula purposes and is rendered alkaline (pH bymeans of potassium carbonate. The reaction product which precipitated inthe form of an oil is extracted with ethyl acetate.

The ethyl acetate solution is dried over anhydrous sodium CHZCHwHWHTN.AZOH sulfate, freed from the solvent under reduced pressure I E and theresidue is dissolved in about 100 cc. anhydrous R methanol. By addingmethanolic hydrochloric acid, the di- R2 hydrochloride of the3-['y-(4-(fl-3,5-trimethoxybenzy y p p U] B yp py 4 R1 R2 z Meltingmint, 0 methyl-7,8-dimethoxy-cournarin is obtained in the form ofcolorless crystals decomposing at 231233 (after re- SE3 ggsg ggiggzggz123-125 crystallization from methanol and water in the ratio of f I Z 22 5 122 w- 7 ssesar ga Yleld: 49 g.=87% of the theoretical. 8% %011:6H 91 225 The 3 ['y (4 (f3 hydroxyethyl) p1peraz1no[1 g Z E ,8 hydroxypropyl] 4 methyl 7,8 dlmethoxy cou- OGHE s 2 2CH2 Hz- 1 135 CH 021150C.H OH 2 240 mal'm required as starting material can be prepared as 3 22 follows: 1 Decomposition point of the dihydrochloride.

9 1O EXAMPLE 3 OCH:

H200 CHa 21o (IJHa (I) O C H:

C Hr!) HCH2N N-CHz-CHa-O-C O- OCH:

l 11:00 O O 0 OH:

OOHa

40.6 g. (0.1 mol) 3-[ y-(4-(,B-hydroxyethyl)piperazino The 3['y-piperazino[1']-}9-hydroxypropyl]-4-meth 1- [1']) 8 hydroxypropyl] 4methyl -7,8 dimethoxy 7,8-dimethoxy-coumarin utilized in the presentexample coumarin are dissolved in 350 cc. anhydrous chloroform asinitial product was prepared as follows: and 20.2 g. (0.2 mol)triethylamine are added. Within 86 g. (1 mol) anhydrous, distilledpiperazine are distwo hours, 46 g. (0.2 mol) 3,4,5-trimethoxybenzoylchlosolved in 150 cc. chloro benzene and heated to 120 with ride,dissolved in 200 cc. anhydrous chloroform are added the addition of 11g. sodium carbonate. To this mixture dropwise with stirring; theinternal temperature rising to a solution of 31 g. (0.1 mol) 3-(-chloro-p-hydroxyabout 50. After the decay of the exothermic reaction,propyl)-4-methyl-7,8-dimethoxy-coumarin in 150 cc. the solution isstirred at 4050 for another 2 hours and chloro benzene is added slowlyand dropwise with stirring. subsequently worked up as described inExample 2. Stirring is continued at 120 for 12 hours. After the mix-Thus, the dihydrochloride of the diester having the genture has beenfiltered off with suction the filtrate is reduced eral formula givenabove is obtained in the form of colorto a small volume in the vacuum,then the major part of less crystals which decompose at 158 (afterrecrystallizathe excess piperazine is distilled off. The residue isadtion from methanol). mixed with water and after the addition ofpotassium Yield: 70 g.=82% of the theoretical. carbonate, extracted withmethylene chloride. After dry- The above-mentioned diester is likewiseobtained by ing, the methylene chloride layer is evaporated to drynessreacting in chloroform the monoester obtained according under reducedpressure. After the mixture has been alto Example 2 with3,4,5-trimethoxy benzoyl chloride by lowed to stand for a while, the3-('y-piperazino[1']-B adding triethylamine. y r xypropyl)4-methyl-7,8-dimethoxy-coumarin crys- 36.2 g. (0.1 mol)3-['y-piperazin0[1]-/5'-hydroxypropylltallizes in the form of colorlessneedles melting at 4-methyl-7,8-dimethoxy-coumarin are dissolved in 100124-126". cc. chlorobenzene and after the addition of 13.8 g. (0.1Yield: 19 g.=52.5% of the theoretical. mol) potassium carbonate, at -60,a solution of 29 g. Analogously to the description given in Examples 2,3 (0.1 mol)'y-cl1loropropy1-3,4,5-trimethoxybenzoate in 50 5 and 4, thefollowing compounds can be prepared under cc. chlorobenzene is addeddropwise with stirring within the present invention: one hour. Thesolution is stirred for 12 hours with heat- G l f fl ing under reflux,it is filtered off from the insolute while hot and the filtrate is freedfrom the solvent in the water- R1 (R3) methoxybenzoxypropyl)piperazino[1']) p hydroxy- L propyl]-4-methyl-7,8-dimethoxy-coumarin isobtained in the form of colorless crystals decomposing at 225.

jet vacuum. After working up as described in Example 2, thedihydrochloride of the 3-['y-(4'-('y-3",4",5-tri- "CHPCIPCHTN 2 l Yield:50 g.-=73% of the theoretical. 75

Melting Point or decomposition point of the di- R1 R, Y -.A a) mhydrochloride,

CH C11 -OH 'CH2CHzCHgCH2 3,4,5-(0CH3)3 248 11C H7 CH O --OH HzC Hr-3,4,5-(0CH3)3 200 110 1-17 CH O OH -CH2CH2CH2 3,4,5-(OCH 195 11C3H7 CHQO--OH CH2CH CH2CH2- 3,4,5(0OH3)3 235 C5115 CHQO OH -0 H CH 3,4,5-(OCH 185CeH5 C H O OH -C HzCHzC Ho 3,4,5-(OCHa)a 215 CaHs C11 0 -OH CH C11201120 H2 3,4,5-(OCH )3 198 OH; OCH; -OC O -0 CH OH O H2CH33,4,5-(OCHa)a 162 OCH CH 0011 Same as above GH2CH(CHa) 3,4,5-(0 CH 151CH OCH; 6 -CHgCHzCHgCHz- 3,4,5-(OCH3)3 16 110 11 OCH -CH2C H23,4,5-(OCH3)3 1G nC H1 0 CH CH2CH2CH2 3,4,5-(OCH )3 l7 1'103H7 OCH3CH2OH(C H3)- 3,4,5-(0CH3)3 17 1103111 OCH; CHzCH OH2C H s,4,5-(0 CH3);17 06115 OCH 2CH2- 3,4,5-(OCH3)3 14 0 115 OCH3 CH C H 6 H2- 3,4,5-(0 CH15 Calls 00113 -CH--(CH 3,4,5-(OCH 14 CaHa OGHQ CH OH CH G H2- 3,4,5(OCH3); 16 1 CH OCHa CH3CH2- 3,5-(OCH3): 160

0 H3 0 CH -CHzCHz- 1-0 CH: 162

CH; 0C3Hli --CH2CHz 3,4,5-(0CH3)3 130 CH; 0 CH3 CHzCHz- 3,4,5- (OCHz);210

0 H3 0 0 Ha -CHzCHz- 3,4,5-(OCH )3 20 EXAMPLE 5 O OH;

OCH&

under reflux for 2 hours and, while hot, separated triethylaminehydrochloride is filtered off with suction. The filtrate is washed withwater, a 5% sodium hydrogen carbonate solution and again with water anddried over anhydrous sodium sulfate. The solvent is now distilled off at50 in the Water-jet vacuum and the residue, a light- 7 yellow, viscousoil, is dissolved in dilute, aqueous hydrochloric acid. For purificationpurposes, the hydrochloric, aqueous solution. is extracted with ethylacetate. The limpid aqueous phase is rendered alkaline with potassiumcarbonate and is again extracted with ethyl acetate. The

OOH:

resultant ethyl acetate solution is washed again with" water, dried overanhydrous sodium sulfate and reduced to a volume of about 50 cc. Theresidue is admixed with ethereal hydrochloric acid until congo paperturns blue. The precipitated dihydrochloride of the 3-[B(4'-(fi-3,4", 5"trimethoxybenzoxyethyl) piperazino-[1])-ethyl]-4-methyl-6,7-dimethoXy-coumarin decomposes at 224 after recrystallizationfrom anhydrous methanol.

Yield: 47 g.=73% of the theoretical.

The 3-[5-(4'-( 3-hydroxyethyl)-piperazino[1'] )-ethyl] 4-methyl-6,7-dimethoxy-coumarin used as starting material can be prepared asfollows:

(a) 13 g. (0.055 mol) 3-(B-hydroxyethyl)-4-methyl-6,7-dihydroxy-coumarin (prepared by condensing 1,2,4-triacetoxy benzenewith m-acetylbutyrolactone, analogously to the method described in Chem.Abstr. 54, 24690 g., (1960)), 40 cc. glacial acetic acid and 36 cc. 48%hydrobromic acid are stirred at -115 for 5 hours. After cooling down,the reaction mixture is poured into the 13 14 fivefold quantity of waterand the precipitate which has methoxy-coumarin is obtained having amelting point of settled out is filtered off with suction. The reactionpro- 128130. duct which is still wet can be recrystallized from glacialYield: 32 g.=85% of the theoretical. acetic acid. Thus, 12 g. (=73% ofthe theoretical) 3-(13- Analogously, the intermediates of the followinggeneral bromo-ethyl)-4-methyl-6, 7-dihydroxy-coumarin are obtainedhaving a melting point of 262. Analogously, the

formula can be synthetized:

General formula:

following products were prepared: R 3-(fl-bromoethyl-1-n-propyl-6,7-dihydroxy-cournarin.

Melting point: 250252. CHsO- CH2(1H2N NA2OH3-(B-brornoethyl)-4-phenyl-6,7-dihydroxy-coumarin. 1O

Melting point: 255. CHsO- O (b) g. (0.05 mol)3-(B-bromoethyl)-4-methyl-6, 7-dihydroxy-coumarin are dissolved in 100cc. dioxan and RI Melting Point, admixed with g., dimethyl sulfate. Whenpassing nitro- 15 gen through this mixture, a solution of 7 g. sodiumhy- :8g6g g $313 droxide in 20 cc. water is added dropwise withstirring, at nCaHr cH2oHT 133-135 -40". Stirring of the reaction mixtureis continued at :8 :E%E 35-40 until it does not show an alkalinereaction any nCgH --CHzCHzCH2CH2- 116-118 longer. Aftena furtheraddition of 25 g di methyl sulfate, 20 82%: :ggiggf gag; again asolution of 7 g. sodium hydroxide in 20 cc. water Car CH2CH(CH 151-152is added dropwise. After the reaction mixture is no longer alkaline itis evaporated to dryness in the water-jet Analo y t0 the descflptlollgiven 111 the P vacuum and the residue is diluted with water. Theprecipiexample, paragraph 1, the following compounds can be tatedreaction product is dissolved in ethyl acetate and the 25 prepared underthe present invention from the aboveethyl acetate layer is washed withdiluted sodium hymentioned intermediates: droxide solution, then driedand evaporated to dryness General formula:

111 OCH3 CHaO- CH2CHN N--Az-OCO -0 CH3 l omo- -0 0011:

under reduced pressure. Thus, 3-(B-bromoethyl)-4- methyl-6,7-dimethoxy-coumarin is obtained in the form dechgltiS1fiigifintio ofcolorless crystals melting at 215216. o ,533,- Yield: 10 g.=6l% of thetheoretical. 1 A2 chloride, 0 Analogously to the process as describedabove, the CH3 186 OH -OH OH CH- 235 following intermediates can beprepared. noaam 5 232 3-(,B-bromoethyl)-4-n-prop3;l 6,7dirnethoxy-coumarln. jggzgggggi" 33g Melting pom-t: 114-117 nC H-on2oH1oH2cH2- 215 3-(B-bromoethyD-4-phenyl 6,7 dimethoxy-coumarin.jggiggia Melting point: 190-191 CrH CHzCH(CH 158 (c) 32.7 g. (0.1 mol)3-(fi-bromoethyl)-4-methyl-6, 7-dimethoxy-coumarin and 13 g. (0.1 mol)N-(B-hy- EXAMPLE 6 OCH:

H300 -0CH3 I 00 (313: I (1)011: H3oo GHQ-(JHCHz-N' NOHzOHzCH2OC o-Qoom lW HsCO \O/O OCHa droxyethyl)-piperazine are dissolved in 100 cc. chloro42.0 g. (0.1mol) 3-['y-(4'-('y-hydroxypropyl)-piperazinobenzene. Afterthe addition of 10.6 g. (0.1 mol) anhy- [l'])/3hydroxypropyl]-4=methyl-6,7-dimethoxy-coumadrous sodium carbonate, thesolution is stirred for 12 rin are dissolved in 300 cc. anhydrouschloroform and hours with boiling under reflux. After cooling down, 20.2g. (0.2 mol) triethylamine are added. Within 2 hours, precipitatedsodium bromide is filtered off with suction a solution of 46 g. (0.2mol) 3,4,5-trimethoxybenzoyl and the filtrate is evaporated to drynessunder reduced chloride in 100 cc. anhydrous chloroform is addeddroppressure. The remaining oily crude product is crystallized Wise withstirring, the internal temperature rising to about by stirring it withlittle ethyl acetate. The crystallized 45. After the decay of theexothermic reaction the soluproduct is filtered off with suction and,for further purifition is stirred at 40-50" for another 2 hours. Thereaction cation, recrystallized from ethyl acetate. Thus, 3-[fi-(4-solution is first washed with water, then with diluteaquehydroxyethyl-piperazino[1'] )-ethyl 4 methyl 6,7 dious sodiumhydrogen carbonate solution and finally again 1 with water and issubsequently worked up as described in Example 5.

The dihydrochloride of the 3-[7-(4'-('y-3",4",5"-trimethoxybenzoxypropyl) piperazino[1] )-fi-3",4",5"-trimethoxybenzoxypropyl] 4-methy1-6,7-dimethoxy-coumarim is obtainedin the form of colorless crystals decomposing at 188.

Yield: '69 g.=78.5% of the theoretical.

The 3- ['y-'(4'- ('y-hydroxypropyl) -piperazino 1'])-fl-hydroxypropyl]-4-methyl-6,7-dimethoxy-coumarin required as startingmaterial can be prepared as follows:

28.4 g. (0.1 mol) 3-['y-chloro-,B-hydroxypropyl]-4-1nethyl-6,7dihydroxy-coumarin (preparedby condensing uacetyl-y-chloromethyl-butyrolactone with1,2,4-triacetoxybenzene analogously to the method described in BritishPat. 1,044,608) are dissolved with heating in 200 cc. dioxan. Aftercooling down to about 40, 40 g. dimethyl sulfate are added. Then, withstirring in a nitrogen atmosphere, a solution of 42 g. potassiumcarbonate dissolved in 8-0 cc. water is added dropwise. The reactionmixture is stirred at 40 until a sample does not shown any longer ayellow tinge when admixed with diluted sodium hydroxide solution, whichis the case after roughly 2-3 hours.

When this mixture is diluted with water, the reaction productprecipitates in the form of colorless needles. For purificationpurposes, the crude product filtered OH? with suction is dissolved inchloroform, the solution is washed With diluted sodium hydroxidesolution and dried. After having evaporated the chloroform solution todryness, the 3-['y-chloro-fl-hydroxypropyl]4-methyl-6,7-dimethoxycoumarin is obtained in the form of colorlessneedles having a melting point of 184185.

Yield: 24.8 g.=79% of the theoretical.

Analogously there are obtained:

3- ['y-chloro-p-hydroxypropyl] 4-n-propyl6,7-dimethoxycoumarin. Meltingpoint: 132.

3-[y-chloro-fi-hydroxypropyl] 4-phenyl-6,7-dimethoxycoumarin. Meltingpoint: 100.

31.2 g. (0.1 mol) 3-('-chloro-fi-hydroxypropyl)-4-methyl-6,7-dimethoxy-coumarin and 14.4 g.N-(y-hydroxypropyl)-piperazine are dissolved in 150 cc. chloro benzeneand, after the addition of 11 g. anhydrous sodium carbonate, stirred at120 for 7 hours. After cooling down, the mixture is filtered oif withsuction from the precipitated sodium chloride and the filtrate isevaporated to dryness under reduced pressure. The crude productcrystallizing out is stirred with 100 cc. ethyl acetate for furtherpurification, filtered off with suction, then vacuum-dried. Thus, 3-['y-(4'-('y-hydroxypropyl) pipera*Zino[1'])-,8-hydroxypropyl] 4methyl-6,7-dimethoxy-coumarin is obtained having a melting point of148-151 Yield: 30 g.=71.5% of the theoretical.

The following intermediates can be prepared analogous- General formula:

CHaO- CHaCH(OH)-OH2N N-Aa-OH 5 CHaO- \O -O B A Melting Point,

0.11 -CH2CHz- 133 05115 'CH2CH(CH3) 1 224-225 06115 0H2CH2CH2CH3 116-11806115 CH2OH2CH2 124 1 As dihydrochloride.

Analogously to the description given in paragraph 1 of the presentexample, the following compounds can be prepared under the presentinvention:

General formula:

R1 OCH;

CHz-fiJH-OHz-N N-Ar-OCO OCH 0 O OCH CHaO OCH:

OCH:

Melting Point or decomposition point the dihydro- R1 Az chloride,

CH3 CH5CH2 158 CH3 -CH2CH(CH3)-- 160 CH; OHzCHgOH CH 130 What is claimedis:

1. New therapeutic coumarin derivatives having the formula wherein R isselected from the group consisting of hydrogen, lower alkyl and phenyl,R is selected from 6,7- and 7,8-positioned alkoxy having 1-4 carbonatoms, R is lower alkoxy having l4 carbon atoms, In is selected from theintegers 1, 2, and 3, A is selected from the straight and branchedalkylene radicals having 23 carbon atoms, A is selected from straightand branched alkylene radicals having 24 carbon atoms, and Y is selectedfrom hydrogen, hydroxy or the radical or hydrochlorides of said coumarinderivatives.

2. coumarin derivatives as set forth in claim 1, wherein R is selectedfrom the group consisting of methyl, propyl and phenyl, R is methoxy in7-8 positions, R is methoxy in 3-4-5-positions, m is 3, A Y is CH CH andA is selected from the group consisting of ethylene, propylene,isopropylene and butylene, or the hydrochlorides of said coumarinderivatives.

3. Coumarin derivatives as set forth in claim 1, wherein R is selectedfrom the group consisting of methyl, propyl and phenyl, R is methoxy in7-8-positions, R is methoxy in 3-4-5-positions, m is 3, A Y is CH CHOHHand A is selected from the group consisting of ethylene, propylene,isopropylene and butylene, or hydrochlorides of said coumarinederivatives.

4. Coumarin derivatives as set forth in claim 1, wherein R is selectedfrom the group consisting of methyl, propyl and phenyl, R is selectedfrom the group consisting of methoxy and ethoxy in 7-8-position, R isselected from the group consisting of methoxy in 3-, 4-, 5-, 3-4, 3-5-,4-5- and 3-4-5-positions, m is selected from the group consisting of1,2, and 3, A is selected from the group consisting of ethylene,propylene, isopropylene and butylene, and A -Y is CHa-(JH-OHA orhydrochloride of said coumarin derivatives.

5. 3-[,B-4-(5-3,4",5" trimethoxybenzoylethyl)piperazino[1']-ethyl]-4-methyl 7,8 dimethoxy-coumarin, or hydrochlorideof said coumarin derivative.

6. 3-[,B-(4-(;3-3, 4", 5 "trimethoxybenzoxypropyl)- piperazino[1])-ethyl]-4-propyl-7-,8 dimethoxy courarin, or hydrochloride of saidcoumarin derivatives.

7. 3-[7-(0c- 3",4",5" trimethoxybenzoxyethyl)-piperazino[1] 5 3",4",5"trimethoxybenzoxypropyl] 4- methyl-7,8-dimethoxy-coumarin, orhydrochloride of said coumarin derivative.

8. 3-[ -(4-(/3-3",4", 5" trimethoxybenzoxyethyl)-pi perazino[1])-,B-3",4", 5"-trimethoxybenzoxypropyl]-4- methyl-7,8-diethoxy-coumarin, orhydrochloride of said coumarin derivative.

9. 3-['y4'-(fl-3",4",5" trimethoxybenzoxyethyl) piperanzino[1])43-3",4"5"-trimethoxybenzoxypropyl] 4 propyl17,8-dimethoXy-coumarin, orhydrochloride of said coumarin derivative.

References Cited Morrison et al.: Organic Chemistry, 1959, p. 483.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner U.S. Cl.X.R. 414250.

